14-3-3 regulates the nuclear import of class IIa histone deacetylases.
Class IIa histone deacetylases (HDACs) form complexes with a class of transcriptional repressors in the nucleus. While screening for compounds that could block the association of HDAC4 with the BTB domain-containing transcriptional repressor Bach2, we discovered that phorbol 12-myristate 13-acetate (PMA) induced the cytoplasmic retention of HDAC4 mutants lacking a nuclear export signal (NES). Although PMA treatment and PKD overexpression has been proposed to facilitate the nuclear export of class IIa HDACs by creating 14-3-3 binding sites containing phosphoserines, our experiments using HDAC mutants demonstrated that PMA greatly reduces nuclear import. PMA treatment repressed the NLS activity in a manner dependent on 14-3-3 binding. These results suggest that nuclear HDAC4 is not tethered in the nucleus, but instead shuttles between the nucleus and the cytoplasm. Phosphorylation-induced 14-3-3 binding biases the balance of nucleo-cytoplasmic shuttling toward the cytoplasm by inhibiting nuclear import.
Nishino
Tomonori G
TG
Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Miyazaki
Masaya
M
Hoshino
Hideto
H
Miwa
Yoshihiro
Y
Horinouchi
Sueharu
S
Yoshida
Minoru
M
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D049790:Nuclear Export Signals / Q000235:genetics; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
D048948:14-3-3 Proteins; D056572:Histone Deacetylase Inhibitors; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D012097:Repressor Proteins; C016658:phorbolol myristate acetate; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D013755:Tetradecanoylphorbol Acetate